It is clear that the effects of cortisol on memory depend on a range of factors, many of which already have been well described elsewhere (e.g., De Quervain et al., 2009
; Roozendaal et al., 2009
; Wolf, 2009
). In this review we aimed to highlight novel findings regarding moderators of cortisol’s effects on memory formation and reconsolidation (for an overview of plausible modulators see ). Further knowledge regarding factors that modulate stress hormone effects on memory may aid in directing future research, and further our understanding of disorders that are characterized by alterations in memory such as PTSD.
Figure 1 Summary of plausible modulators and their interactions with cortisol effects on memory. Genetic polymorphisms, past experiences, dispositional characteristics, situational characteristics (like context and timing) together contribute to the way cortisol (more ...)
The described findings on the role of the GR and MR in emotional memory and cortisol reactivity point to a role of these receptors and their genetic variations in emotional memory processes. Future research should address the impact of the genetic variability of the entire GR- and MR-gene (haplotypes as opposed to single variations). Given the fact that corticosteroid effects take place through the transcriptional regulation of specific sets of MR and GR genes it is likely that these genes may be associated with strength and direction of cortisol effects on memory. However, to date, no human studies have directly tested whether certain genetic predispositions may alter cortisol effects on memory. Moreover, even with the same set of genes, epigenetic modification of expression of a variety of cortisol-related genes may take place. Findings especially point to early life stress as a plausible mechanism through which corticosteroid’s effects on learning are altered. Thus, apart from gene x gene interactions, gene x environment interactions should be investigated. Not only GR- and MR-genes but also other genes related to the HPA axis and the noradrenergic system might contribute to variations in corticosteroid effects on emotional memory. Related to this, trait characteristics such as dispositional arousal are likely to play an important role in memory modulation by cortisol, but few studies have examined the relation between variability in cortisol effects on memory and inter-individual differences in lasting characteristics. The inclusion of relevant assessments of personal characteristics such as affective style or past experiences could be a good starting point in future research to explore the moderating role of dispositional characteristics in cortisol effects on memory. From a clinical perspective, such variables together might be able to explain, at least in part, why some individuals are more susceptible to develop psychiatric symptoms after adverse life events or trauma.
Recent data have also shown situational characteristics add to the variability in cortisol effects on memory. Findings that cortisol modulates the contextual dependency of memories have important implications for studies investigating stress and/or associated stress hormone effects on memory consolidation. Possibly, stress alters the ability to use cues from the environment to retrieve the central memories, perhaps resulting in more gist-like memories (e.g., Nadel and Payne, 2002
). On a broader level, stress hormone effects on the contextual dependency of memories may have implications for (etiological) mechanisms of PTSD. Patients suffering from post-traumatic stress disorder (PTSD) display enhanced memories for central cues, along with reduced memory for cues in the traumatic context (Elzinga and Bremner, 2002
). Therefore, theories of PTSD emphasize impairment in the ability to store fearful memories into their original encoding context (e.g., Ehlers and Clark, 2008
), or a more general impairment in the behavioral modulation by contextual cues (e.g., Liberzon and Sripada, 2008
Another situational modulator may be the time lag in between cortisol elevation and a learning experience. Several theories (Diamond et al., 2007
; Joëls et al., 2011
; Richter-Levin and Akirav, 2003
) predict differential effects by corticosteroids in the time-domain shortly after stress as opposed to several hours later. However, not many human studies have taken this factor into account. Several pioneering studies suggest that timing is an important factor to be aware of when designing future studies investigating stress effects on memory.
Studies investigating brain regions mediating cortisol effects on memory have suggested that the MTL, particularly the hippocampus, is involved. However, the hippocampus does not work alone, and action of amygdala and other structures in conjunction with the hippocampus may also take place. The behavioral effects of cortisol on memory are widespread and sensitive to a number of variables, such as interaction with arousal. It is thus plausible that, with increasing knowledge, this complexity is likely to be reflected in underlying and interacting brain regions, which are yet to be fully understood. Thus, research examining connectivity among structures during memory formation will be essential to determine the role of the hippocampus within the larger network of structures responsible for glucocorticoid effects on memory. In addition, future research must address potential moderating effects of variables enumerated above (e.g., personal characteristics, emotional arousal, timing, and context) on glucocorticoids’ effects on the neural circuitry of memory.
As described in the final part of this review, it has become clear that memory traces are not permanent after they have initially been established, as was assumed in the classical view of memory. Recent studies have shown that when a memory is retrieved, the underlying memory trace is labile and can be modified. Cortisol is one of the agents able to modulate reactivated memories, but one must keep in mind that other pharmacological (i.e., propranolol) and environmental (i.e., a stressor or interference learning) agents have also been successfully used. Further research may aid in understanding processes that contribute to the maintenance of traumatic memories or reveal ways of disrupting an earlier acquired fear memory by (pharmacologically) blocking reconsolidation, that could have significant clinical implications (e.g., Kindt et al., 2009
From the modulators of cortisol effects on memory as discussed in this review it becomes clear that many factors that have received relatively little attention in the scientific literature contribute to cortisol’s role in memory consolidation. Furthermore, the modulators of cortisol’s effects described herein undoubtedly interact with one another. As a consequence of our increasing understanding of many possible modulators, numerous interesting questions arise that can be addressed in future research. For instance, ‘Are individuals who have suffered from childhood trauma more prone to store emotional memories in a decontextualized fashion due to cortisol?’ and ‘Is the interplay between cortisol, genetic susceptibility and certain personal characteristics associated with BOLD fMRI signal changes in the hippocampus when storing a memory?’ In order to answer such a wealth of complex questions, future research may profit from analysis techniques that can take into account several levels of variables, instead of focusing on just a few at the same time. For instance, multilevel approaches provide a powerful way to simultaneously assess the contribution of genetic background, individual differences in trait characteristics, hippocampal reactivity and childhood experience to predict memory. Further, cortisol timing and contextual variables can be added to such a model as well. Finally, it can be investigated whether first level relationships might be moderated by second level variables. Perhaps even more versatile, structural equation modeling (SEM) provides estimates, or path coefficients, which indicate the direction and significance of the association between constructs, as well as several fit indices which evaluate the fit of any proposed model.
In conclusion, the factors described herein may explain important variability in corticosteroid effects on memory. These factors should be taken into account in studies examining corticosteroid effects on memory. Many interesting questions remain to be answered that perhaps require sophisticated analytical techniques in order to provide a nuanced picture of the way stress and cortisol interact with several moderators to affect long-term memories, and how these again can be modulated once established. Knowledge regarding ways in which genetics, lasting characteristics, and other variables moderate cortisol’s effects on memory consolidation and/or reconsolidation can serve as a foundation for treatment research, which could further elucidate the potential therapeutic benefits of manipulating neural signaling of corticosteroids.